Generic Name	Trade Name	Route	Mechanism	Indications	Major Adverse Effects
HORMONAL THERAPIES
Antiestrogens
Tamoxifen	Nolvadex	PO	Blockade of estrogen receptors	ER-positive breast cancer in pre- and postmenopausal women	Increased risk of endometrial cancer and thrombosis Hot flushes, fluid retention, vaginal discharge, nausea, vomiting, and menstrual irregularities
Toremifene	Fareston	PO	Blockade of estrogen receptors	ER-positive breast cancer in postmenopausal women only
Fulvestrant	Faslodex	IM	Blockade of estrogen receptors	ER-positive breast cancer in postmenopausal women only
Aromatase Inhibitors
Anastrozole	Arimidex	PO	Inhibition of estrogen synthesis	ER-positive breast cancer in postmenopausal women only	Musculoskeletal pain, osteoporosis and related fractures
Letrozole	Femara	PO
Exemestane	Aromasin	PO
OTHER DRUGS FOR BREAST CANCER
Anti-HER2 Antibody
Trastuzumab	Herceptin		Blockade of HER2 receptors	HER2-positive breast cancer in pre- and postmenopausal women	Cardiotoxicity and hypersensitivity reactions
Kinase Inhibitor
Lapatinib	Tykerb	PO	Inhibits HER2 tyrosine kinase and EGFR tyrosine kinase	HER2-positive breast cancer in pre- and postmenopausal women	Diarrhea, hepatotoxicity, cardiotoxicity, interstitial lung disease
Cytotoxic Drugs (Representative Agents)
Doxorubicin plus cyclophosphamide	Adriamycin, Cytoxan, Neosar		Direct cell kill by DNA intercalation, topoisomerase II inhibition, and DNA alkylation	Breast cancer in all women, regardless of ER, HER2, or menopausal status	Together, these drugs can cause cardiotoxicity, bone marrow suppression, alopecia, oral and GI ulceration, and hemorrhagic cystitis
Paclitaxel	Taxol, Onxol, Abraxane		Direct cell kill by mitotic arrest	Breast cancer in all women, regardless of ER, HER2, or menopausal status	Bone marrow suppression, peripheral neuropathy, alopecia, cardiotoxicity, muscle and joint pain Severe hypersensitivity reactions with Taxol and Onxol, but not Abraxane
Eribulin	Halaven	IV	Direct cell kill by mitotic arrest	Breast cancer in all women, regardless of ER, HER2, or menopausal status	Bone marrow suppression, peripheral neuropathy
Drugs to Delay Skeletal Events
Denosumab	Xgeva*	SubQ	Inhibits osteoclast function and production	Hypercalcemia of malignancy, prevention of malignancy-related skeletal events	Hypocalcemia, serious infections, skin reactions, osteonecrosis of the jaw
Zoledronate	Zometa^†	IV	Inhibits osteoclast function	Hypercalcemia of malignancy, prevention of malignancy-related skeletal events	Kidney damage, osteonecrosis of the jaw

EGFR = epidermal growth factor receptor, ER = estrogen receptor, HER2 = human epidermal growth factor receptor 2.

^*Denosumab is also available as Prolia for treating postmenopausal osteoporosis.

^†Zoledronate is also available as Reclast for treating osteoporosis and Paget’s disease.

Hormonal agents for breast cancer fall into two major groups: antiestrogens (eg, tamoxifen [Nolvadex]) and aromatase inhibitors (eg, anastrozole [Arimidex]). Antiestrogens block receptors for estrogen, whereas aromatase inhibitors block estrogen biosynthesis. In both cases, tumor cells are deprived of the estrogen they need for growth. However, there is a caveat: For these drugs to work, tumor cells must have estrogen receptors (ERs). Fortunately, the majority of breast cancers are ER positive. For years, tamoxifen had been the hormonal agent of choice. However, recent data have shown that, in postmenopausal patients, aromatase inhibitors are more effective, both in the metastatic and adjuvant setting. There is a wealth of data showing that adjuvant hormonal therapy can reduce tumor recurrence and prolong life.

In addition to chemotherapy and hormonal therapy, two other drugs—trastuzumab [Herceptin] and lapatinib [Tykerb]—can be used for adjuvant treatment. Trastuzumab blocks receptors known as HER2, and lapatinib inhibits two enzymes, known as HER2 tyrosine kinase and EGFR tyrosine kinase. Both drugs are indicated only for cancers that are HER2 positive. As discussed later in the chapter, one more drug—bevacizumab [Avastin]—had been approved for breast cancer, but the indication was rescinded in 2011. Why? Because in postmarketing studies, bevacizumab failed to show significant benefit.

Lastly, patients may take denosumab [Xgeva] or zoledronate [Zometa] to minimize hypercalcemia (caused by bone metastases) and fractures (caused by bone metastases as well as hormonal therapy).

What about breast cancer prevention? Currently, two drugs are approved for preventing breast cancer in women at high risk. Both drugs are selective estrogen receptor modulators, or SERMS. One of the drugs—raloxifene [Evista]—is approved only for postmenopausal women. The other drug—tamoxifen [Nolvadex]—is approved for premenopausal and postmenopausal women. In clinical trials, these drugs reduced the risk of breast cancer by about 50%. However, they both pose a risk of thrombosis, and tamoxifen also poses a risk of endometrial cancer. Nonetheless, in women at high risk for breast cancer, the benefits of these drugs outweigh the risks. Raloxifene is discussed in Chapter 75. Tamoxifen is discussed below. Two other drugs—exemestane [Aromasin] (discussed below) and lasofoxifene [Oporia]—can also prevent breast cancer, but are not yet approved for this use.

Anastrozole

Mechanism, use, and dosage.

Anastrozole [Arimidex] is approved for first-line oral therapy of postmenopausal women with early or advanced ER-positive breast cancer. The drug works by depriving breast cancer cells of estrogen. In postmenopausal women, the major source of estrogen is adrenal androgens, which are converted into estrogen by the enzyme aromatase in peripheral tissues. Anastrozole inhibits aromatase, and thereby reduces estrogen production. With regular use, the drug lowers estrogen to undetectable levels. In women with estrogen-dependent cancer, estrogen deprivation can arrest tumor growth, and may cause outright cell death. In clinical trials, anastrozole was not effective in women with ER-negative tumors or in women who did not respond initially to tamoxifen. The recommended dosage is 1 mg PO once a day. Treatment duration typically ranges from 2 to 5 years. Anastrozole may be used as initial therapy, or as a follow-up to therapy with tamoxifen.

Adverse effects.

Anastrozole is generally well tolerated. In clinical trials, about 5% of patients withdrew because of adverse effects. At a daily dose of 1 mg, the most common adverse effects are musculoskeletal pain, asthenia, headache, and menopausal symptoms, including hot flushes, vaginal dryness, and GI disturbances. Other reactions include anorexia, vomiting, diarrhea, constipation, dyspnea, peripheral edema, vaginal hemorrhage, and hypertension.

Up to 50% of women experience musculoskeletal pain, often described with the phrase “every bone in my body hurts.” The cause may be estrogen deprivation. Persistent or severe pain drives about 5% of users to discontinue treatment. For women who choose to continue anastrozole, pain can often be managed with a mild analgesic (eg, acetaminophen, ibuprofen). High-dose vitamin D may help too.

Estrogen depletion increases the risk of osteoporosis and related fractures. To reduce bone loss, women should ensure adequate intake of calcium and vitamin D. Women at high risk should take a bisphosphonate (eg, zoledronate [Zometa]) or denosumab [Prolia].

Comparison with tamoxifen.

As shown in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, which enrolled postmenopausal women with early breast cancer, anastrozole is more effective than tamoxifen and causes fewer adverse effects. After a median follow-up of 5.6 years, cancer recurred in 13% fewer of the women who took anastrozole, and the time to cancer recurrence was longer. Regarding side effects, anastrozole is less likely to cause hot flushes, weight gain, or vaginal bleeding—although it may cause more nausea and irritability. In contrast to tamoxifen, anastrozole is devoid of all estrogenic activity, and hence does not promote endometrial cancer or thromboembolic events—although it does increase the risk of fractures. Because of their superior efficacy and tolerability, aromatase inhibitors have replaced tamoxifen as the drug of first choice for treating ER-positive breast cancer in postmenopausal women.

Letrozole

Letrozole [Femara], a selective aromatase inhibitor, is indicated for (1) first-line therapy of early and advanced ER-positive breast cancer in postmenopausal women, and (2) extended adjuvant therapy of early breast cancer following 5 years of adjuvant therapy with tamoxifen. Like anastrozole, letrozole blocks conversion of androgens into estrogens, and thereby deprives breast cancer cells of estrogen’s growth-promoting influence. In one study of women with advanced breast cancer, letrozole (2.5 mg/day) was more effective than tamoxifen (20 mg/day): the objective response rate with letrozole was higher (30% vs. 20%) and the time to tumor progression was longer (9.4 months vs. 6 months). In women with early breast cancer who have received 5 years of tamoxifen therapy, following with letrozole reduces the risk of recurrence. Letrozole’s most common adverse effects are musculoskeletal pain (21%) and nausea (13%). Reactions that occur in 6% to 9% of patients include headache, arthralgia, fatigue, constipation, dyspnea, cough, vomiting, diarrhea, and hot flushes. Extremely low doses are embryotoxic and fetotoxic in animals. Like anastrozole, and unlike tamoxifen, letrozole poses no risk of endometrial cancer. However, it can cause osteoporosis and fractures, and, rarely, thromboembolism. Osteoporosis can be managed with denosumab [Prolia] or a bisphosphonate (eg, zoledronate [Zometa]). No significant drug interactions have been reported.

Exemestane

Exemestane [Aromasin] is indicated for oral therapy of (1) advanced ER-positive breast cancer in postmenopausal women whose disease has progressed despite treatment with tamoxifen, and (2) early ER-positive breast cancer in postmenopausal women who have received 2 to 3 years of tamoxifen therapy and then are switched to adjuvant exemestane to complete a 5-year course of treatment. Like anastrozole, exemestane inhibits aromatase, and thereby reduces estrogen levels. A dosage of 25 mg once daily (administered after a meal) reduces circulating estrogen by 85% to 95%. In the absence of sufficient estrogen, estrogen-dependent tumors cannot thrive. In clinical trials, the objective response rate was about 25%.

In addition to treating breast cancer, exemestane can be effective for breast cancer prevention, as shown in the Mammary Prevention 3 trial, reported in 2011. The trial enrolled 4560 postmenopausal women at high risk for breast cancer, and randomized them to receive exemestane or placebo. The result? After a median follow-up of 35 months, the incidence of invasive breast cancer was 65% lower in the exemestane group. If exemestane is approved for breast cancer prevention, it will become an attractive alternative to raloxifene and tamoxifen.

Exemestane is rapidly absorbed following oral dosing, and is widely distributed to tissues. In the liver, the drug undergoes extensive metabolism, mainly by CYP3A4. Excretion is via the urine and feces. Its half-life is about 24 hours.

Exemestane is generally well tolerated. The most common adverse effects are fatigue (22%), nausea (18%), hot flushes (13%), depression (13%), and weight gain (8%). Like anastrozole and letrozole, exemestane often causes musculoskeletal pain. Increased risk of osteoporosis and fractures is a concern. Women at high risk of osteoporosis can be treated with denosumab [Prolia] or a bisphosphonate (eg, zoledronate [Zometa]).

Drugs that induce CYP3A4 (eg., phenytoin, phenobarbital, rifampin, St. John’s wort) can cause a significant drop in exemestane levels. Accordingly, if these drugs are combined, exemestane dosage may need to increase.

Trastuzumab

Actions and use.

Trastuzumab [Herceptin] is a monoclonal antibody originally approved for HER2-positive metastatic breast cancer and for adjuvant therapy of HER2-positive breast cancer. In 2011, trastuzumab received a new indication: HER2-positive metastatic gastric cancer. Discussion here is limited to breast cancer.

Trastuzumab is only effective against tumors that overexpress human epidermal growth factor receptor 2 (HER2), a transmembrane receptor that helps regulate cell growth. Trastuzumab binds with HER2 and thereby (1) inhibits cell proliferation and (2) promotes antibody-dependent cell death. Between 25% and 30% of metastatic breast cancers produce excessive HER2. High numbers of HER2 receptors are associated with unusually aggressive tumor growth. For treatment of breast cancer, trastuzumab may be used (1) alone in women who failed to respond to prior chemotherapy, (2) in combination with paclitaxel as first-line therapy, and (3) for adjuvant treatment as part of a regimen containing doxorubicin, cyclophosphamide, and paclitaxel.

Clinical trials.

In one trial involving women with metastatic disease, treatment with trastuzumab alone produced a complete response in 3% of patients, and a partial response (more than 50% tumor regression) in 14% of patients. In a trial reported in 2005, chemotherapy alone—doxorubicin plus cyclophosphamide, followed by paclitaxel—was compared with chemotherapy plus trastuzumab. The result? Adding trastuzumab to the regimen produced a significant increase in 3-year disease-free survival (87% vs. 75% with chemotherapy alone), and also produced a significant reduction in 3-year mortality. These data suggest that trastuzumab should be considered for most women who have HER2-positive disease.

Adverse effects.

The principal concern with trastuzumab is cardiotoxicity, manifesting as ventricular dysfunction and congestive heart failure. In clinical trials, the incidence of symptomatic heart failure was 7% with trastuzumab alone, and 28% when trastuzumab was combined with doxorubicin, a drug with prominent cardiotoxic actions. Combining trastuzumab with paclitaxel can also result in cardiac damage. Because of cardiotoxicity, trastuzumab should be used with caution in women with pre-existing heart disease. Concurrent use with doxorubicin and other anthracyclines should generally be avoided. In contrast to the cytotoxic anticancer drugs, trastuzumab does not cause bone marrow suppression or alopecia.

Many patients experience a flu-like syndrome, which also occurs with other monoclonal antibodies. Symptoms include chills, fever, pain, weakness, nausea, vomiting, and headache. The syndrome develops in 40% of patients receiving their first infusion, and then diminishes with subsequent infusions.

Postmarketing reports indicate that trastuzumab can cause potentially fatal hypersensitivity reactions, infusion reactions, and pulmonary events. Symptoms include urticaria, bronchospasm, angioedema, hypotension, dyspnea, wheezing, pleural effusions, pulmonary edema, and hypoxia requiring oxygen. Most severe reactions developed in association with the first dose, either during the infusion or by 12 hours after. If symptoms develop during the infusion, the infusion should be stopped. Death has occurred primarily in patients with pre-existing pulmonary disorders. Accordingly, patients with compromised pulmonary function should be managed with extreme caution.

Dosage and administration.

Treatment consists of a loading dose (2 mg/kg infused over at least 30 minutes) followed by weekly maintenance doses (2 mg/kg infused over 30 minutes). An alternative regimen uses a larger loading dose (8 mg/kg), and larger but less frequent maintenance doses (6 mg/kg every 3 weeks).

Lapatinib

Actions and use.

Lapatinib [Tykerb] is an oral inhibitor of two enzymes—HER2 tyrosine kinase and epidermal growth factor receptor (EGFR) tyrosine kinase—that are involved in cell signal transduction. Enzyme inhibition results in apoptosis and suppression of tumor cell growth. Lapatinib is approved for treating advanced HER2-positive breast cancer, but only in combination with either (1) capecitabine (in patients who have received prior therapy with multiple drugs, including an anthracycline, a taxane, and trastuzumab) or (2) letrozole (in postmenopausal women for whom estrogen deprivation therapy is indicated). EGFR tyrosine kinase is discussed further below under EGFR Tyrosine Kinase Inhibitors.

Adverse effects.

The most common adverse effects of lapatinib plus capecitabine are GI disturbances (diarrhea, nausea, vomiting), fatigue, rash, and palmar-plantar erythrodysesthesia (swelling and numbness of the hands and feet). The most common adverse effects of lapatinib plus letrozole are diarrhea, rash, nausea, and fatigue. Diarrhea occurs in 65% of patients, and is the most common reason for stopping treatment. Like other HER2 inhibitors, lapatinib may pose a risk of cardiotoxicity. Accordingly, the drug should be used with caution in patients with existing cardiac impairment. Rarely, letrozole has been associated with severe liver injury. Liver function tests should be performed at baseline and periodically throughout treatment. When used alone and together with other drugs, letrozole has been associated with interstitial lung disease and pneumonitis. In laboratory animals, giving letrozole during pregnancy resulted in death of the pups a few days after birth. Women using the drug should avoid getting pregnant.

Drug interactions.

Lapatinib is metabolized by CYP3A4, and hence CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s wort) can lower lapatinib levels, and CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, indinavir, nelfinavir) can raise lapatinib levels. If possible, CYP3A4 inducers and inhibitors should be avoided.

Preparations, dosage, and administration.

Lapatinib [Tykerb] is supplied in 250-mg tablets for oral dosing without food (either 1 hour before a meal or 1 hour after). Two dosing regimens are used:

• Lapatinib with capecitabine—The recommended dosage is 1250 mg (5 tablets) taken once every day, along with capecitabine (2000 mg/m²), taken once a day on days 1 through 14 of a repeating 21-day cycle.

• Lapatinib with letrozole—The recommended dosage is 1500 mg (6 tablets) taken once every day, along with letrozole (2.5 mg) taken once every day.

Cytotoxic drugs (chemotherapy)

Cytotoxic drugs may be used before breast surgery or after. When used before surgery, chemotherapy can shrink large tumors, thereby permitting lumpectomy in women who would otherwise require a mastectomy. When used after surgery, chemotherapy can kill cancer cells that remain in the breast, as well as cells that may have metastasized to distant sites. A common regimen for breast cancer consists of doxorubicin (an anthracycline-type anticancer antibiotic) plus cyclophosphamide (an alkylating agent) followed by paclitaxel (a mitotic inhibitor). Representative cytotoxic drugs are presented in Table 103-1.

Denosumab and bisphosphonates for skeletal-related events

Women with breast cancer are at risk for skeletal-related events (SREs), especially hypercalcemia and fractures. There are two causes: the cancer itself and the drugs used for treatment. In breast cancer, most metastases occur in bone. These metastases promote hypercalcemia by increasing the activity of osteoclasts, the cells that promote bone resorption. Not only does resorption promote hypercalcemia, it weakens bone, and thereby increases the risk of fractures. Fracture risk is further increased by use of antiestrogens and aromatase inhibitors. Why? As we discussed in Chapter 61, estrogens promote bone health by inhibiting bone resorption and promoting bone deposition. Hence, by removing the influence of estrogen, the antiestrogens and aromatase inhibitors accelerate bone resorption and reduce bone deposition. Both actions weaken bone, and thereby increase the risk of fractures. To reduce the risk of SREs, we can treat patients with denosumab or a bisphosphonate (usually zoledronate).

Zoledronate and other bisphosphonates

In women with breast cancer, bisphosphonates can help preserve bone integrity, and can thereby decrease the risk of hypercalcemia and fractures. Benefits derive from inhibiting the activity of osteoclasts. At this time, two bisphosphonates—zoledronate [Zometa] and pamidronate [Aredia]—are approved for hypercalcemia of malignancy, and one of them—pamidronate—is also approved for managing osteolytic bone metastases. However, although zoledronate is not approved for osteolytic bone metastases, it is just as effective as pamidronate. Furthermore, compared with pamidronate, zoledronate has three advantages: onset is faster, duration is longer, and infusion time is shorter (15 minutes vs. 2 to 4 hours). Accordingly, zoledronate is generally preferred to pamidronate. Principal adverse effects of the bisphosphonates are kidney damage and osteonecrosis of the jaw.

In addition to reducing fractures and hypercalcemia, bisphosphonates may actually prevent metastases and prolong life. These benefits were discovered somewhat by accident. In women with breast cancer, bisphosphonates were originally employed to suppress bone resorption caused by metastases. While using bisphosphonates for this purpose, researchers noted something surprising: Bisphosphonates appeared to reduce the incidence of new bony metastases. Results of a follow-up study confirmed the original observation: In women with breast cancer, treatment with a bisphosphonate reduced metastases to bone and prolonged survival. These results were obtained using clodronate, an oral bisphosphonate available in Europe and Canada. However, other bisphosphonates should also be effective.

How do bisphosphonates suppress metastases? When cancer cells spread to bone, they stimulate the activity of osteoclasts, the cells responsible for bone resorption. In turn, osteoclasts release growth factors that stimulate the cancer cells, thereby setting up a self-reinforcing cycle. Bisphosphonates interrupt the cycle by inhibiting osteoclast function and blocking tumor adhesion to bone.

The basic pharmacology of the bisphosphonates is discussed in Chapter 75.

Denosumab

Denosumab, marketed as Xgeva, is indicated for preventing (delaying) SREs in patients with breast cancer and other solid tumors that have metastasized to bone. Benefits derive from inhibiting the formation and function of osteoclasts. Efficacy was demonstrated in three double-blind trials that compared denosumab with zoledronate. One trial enrolled patients with breast cancer, one enrolled patients with prostate cancer, and one enrolled patients with other cancers, including multiple myeloma, kidney cancer, small cell lung cancer, and non-small cell lung cancer. Patients received either denosumab (120 mg subQ every 4 weeks) or zoledronate (4 mg IV every 4 weeks). The results? In patients with breast cancer or prostate cancer, denosumab was superior to zoledronate at delaying SREs. In patients with other cancers, denosumab was equal to zoledronate at delaying SREs. Principal adverse effects of denosumab are hypocalcemia, serious infections, skin reactions, and osteonecrosis of the jaw. The pharmacology of denosumab is presented in Chapter 75.

Drugs for prostate cancer

Cancer of the prostate is the most common cancer among men in the United States. In 2011, an estimated 240,890 new cases were diagnosed, and 33,720 were fatal. For men with localized prostate cancer, the preferred treatments are surgery and radiation, with or without adjunctive use of drugs. For men with metastatic prostate cancer, drug therapy and castration are the only options. Among the drugs employed, agents for androgen deprivation therapy (ADT) comprise the largest and most widely used group. The only other choices are cytotoxic drugs and a new immunotherapy known as sipuleucel-T [Provenge]. As with breast cancer, most metastases (65% to 75%) go to bone. To minimize hypercalcemia and fractures caused by bone metastases, men may take zoledronate [Zometa] or denosumab [Xgeva] (see discussion of breast cancer above). The drugs used to treat prostate cancer are summarized in Table 103–2.

TABLE 103–2

Drugs for Prostate Cancer

Generic Name	Trade Name	Route	Major Adverse Effects
DRUGS FOR ANDROGEN DEPRIVATION THERAPY
GnRH Agonists*
Leuprolide	Lupron, Lupron Depot	IM	Hot flushes, erectile dysfunction, decreased libido, decreased muscle mass, gynecomastia, osteoporosis
	Eligard	SubQ
	Viadur	SubQ implant
Triptorelin	Trelstar	IM
Goserelin	Zoladex	SubQ
Histrelin	Supprelin LA, Vantas	SubQ implant
GnRH Antagonist
Degarelix	Firmagon	SubQ	Same as the GnRH agonists plus hepatotoxicity
Androgen Receptor Blockers
Flutamide	Eulexin	PO	Same as the GnRH agonists plus hepatotoxicity
Bicalutamide	Casodex	PO	Same as the GnRH agonists plus hepatotoxicity
Nilutamide	Nilandron, Anandron	PO	Same as the GnRH agonists plus hepatotoxicity and interstitial pneumonitis
CYP17 Inhibitor
Abiraterone	Zytiga	PO	Same as the GnRH agonists plus hepatotoxicity, edema, hypertension, hypokalemia, glucocorticoid insufficiency
OTHER DRUGS FOR PROSTATE CANCER
Immunotherapy
Sipuleucel-T	Provenge	IV	Infusion reactions, fatigue, fever
Cytotoxic Drugs
Cabazitaxel	Jevtana	IV	Neutropenia, hypersensitivity reactions, diarrhea
Docetaxel	Taxotere	IV	Neutropenia, anemia, hypersensitivity reactions, fluid retention
Estramustine	Emcyt	PO	Gynecomastia, thrombosis
Drugs to Delay Skeletal Events
Denosumab	Xgeva^†	SubQ	Hypocalcemia, serious infections, skin reactions, osteonecrosis of the jaw
Zoledronate	Zometa^‡	IV	Kidney damage, atrial fibrillation, osteonecrosis of the jaw

^*Gonadotropin-releasing hormone agonists, also known as luteinizing hormone–releasing hormone (LHRH) agonists.

^†Denosumab is also available as Prolia for treating postmenopausal osteoporosis.

^‡Zoledronate is also available as Reclast for treating osteoporosis and Paget’s disease.

Androgen deprivation therapy

The term androgen deprivation therapy refers to the use of castration and/or drugs to deprive prostate cancers of the androgens they need for growth. By implementing ADT, we can slow disease progression and increase comfort. Initially, ADT was reserved for patients with metastatic disease. However, ADT is now used as an adjuvant in earlier stage disease. Unfortunately, the benefits of ADT are time limited: After 18 to 24 months of treatment, disease progression often resumes. Side effects of ADT include hot flushes, reduced libido, erectile dysfunction, gynecomastia, decreased muscle mass, and decreased bone mass with associated increased risk of fractures.

Where do androgens come from? And how can we reduce their influence? About 90% of circulating androgens are produced by the testes. The remaining 10% are produced by the adrenals and by the prostate cancer itself. Accordingly, we can reduce the influence of androgens in three ways. Specifically, we can block testosterone receptors with drugs; we can lower testosterone production with drugs; and we can lower testosterone production by castration. Drug therapy is more effective than castration. Why? Because castration only eliminates testicular androgens, leaving androgen synthesis by the adrenals and cancer cells intact. In contrast, by using drugs to block testosterone receptors and testosterone synthesis, we can reduce the influence of testosterone from all sources (testes, adrenals, prostate cancer).

Gonadotropin-releasing hormone agonists

The gonadotropin-releasing hormone (GnRH) agonists suppress production of androgens by the testes—but not by the adrenals and prostate cancer cells. Currently, four GnRH agonists are available: leuprolide, triptorelin, goserelin, and histrelin. All four are indicated for cancer of the prostate. In addition, leuprolide is used for endometriosis (see Chapter 63).

Leuprolide

Therapeutic use.

Leuprolide [Eligard, Lupron, Lupron Depot, Viadur] is a synthetic analog of GnRH, also known as luteinizing hormone–releasing hormone (LHRH). Leuprolide is indicated for advanced carcinoma of the prostate. Palliation is the primary benefit. For patients with prostate cancer, leuprolide represents an alternative to orchiectomy (surgical castration). Leuprolide may be administered daily (subQ); monthly (IM); every 3, 4, or 6 months (IM); or once a year (subQ implant).

Mechanism of action.

Cells of the prostate, both normal and neoplastic, are androgen dependent. Leuprolide provides palliation by suppressing androgen production in the testes. During the initial phase of treatment, leuprolide mimics GnRH. That is, the drug acts on the pituitary to stimulate release of interstitial cell–stimulating hormone (ICSH), which acts on the testes to increase production of testosterone. As a result, there may be a transient “flare” in prostate cancer symptoms. However, with continuous exposure to leuprolide, GnRH receptors in the pituitary become desensitized. As a result, release of ICSH declines, causing testosterone production to decline too. After several weeks of treatment, testosterone levels are equivalent to those seen after surgical castration. Because leuprolide therapy mimics the effects of orchiectomy, treatment is often referred to as chemical castration.

It is important to note that leuprolide does not decrease production of androgens made by the adrenals or by the prostate cancer itself. As noted, these nontesticular sources account for about 10% of the androgens in circulation. Hence, even though production of testicular androgens is essentially eliminated, adrenal and prostatic androgens can still provide some support for prostate cancer cells.

Co-treatment with an androgen receptor blocker.

In patients receiving leuprolide, an androgen receptor blocker can help in two ways. Specifically, (1) it can prevent cancer cells from undergoing increased stimulation during the initial phase of GnRH therapy, when androgen production is increased; and (2) it can block the effects of adrenal and prostatic androgens, whose production is not reduced by GnRH agonists. The current trend is to use an androgen receptor blocker during the first weeks of leuprolide therapy (to prevent leuprolide-induced tumor flare), after which the drug is discontinued unless there is tumor progression despite continued leuprolide treatment.

Adverse effects.

Leuprolide is generally well tolerated. Hot flushes are the most common adverse effect, but these usually decline as treatment continues. Reduced testosterone may also lead to erectile dysfunction, loss of libido, gynecomastia, reduced muscle mass, new-onset diabetes, myocardial infarction, and stroke. During the initial weeks of treatment, elevation of testosterone levels may aggravate bone pain and urinary obstruction caused by prostate cancer. As a result, patients with vertebral metastases or pre-existing obstruction of the urinary tract may find treatment intolerable. As noted, concurrent treatment with an androgen receptor blocker can minimize these problems.

By suppressing testosterone production, leuprolide may increase the risk of osteoporosis and related fractures. Bone loss can be minimized by consuming adequate calcium and vitamin D, and by performing regular weight-bearing exercise. In addition, a bisphosphonate (eg, zoledronic acid [Zometa]) or denosumab [Xgeva] can be used to preserve bone and reduce fracture risk (see below).

Preparations, dosage, and administration.

Leuprolide is supplied in three basic formulations for parenteral dosing:

• Leuprolide short-acting injection [Lupron] is supplied as a 5-mg/mL solution for IM administration. The recommended dosage is 1 mg once a day.

• Leuprolide depot injection is available in single-dose kits under two trade names: Lupron Depot (for IM injection) and Eligard (for subQ injection). With either product, the dosage is 7.5 mg once a month, 22.5 mg every 3 months, 30 mg every 4 months, or 45 mg every 6 months.

• Leuprolide implant, sold as Viadur, is formulated as a 65-mg pellet for subQ implantation in the inner aspect of the upper arm once every 12 months.

Triptorelin, goserelin, histrelin

Triptorelin, goserelin, and histrelin are GnRH analogs indicated for palliative treatment of advanced prostate cancer. All three have the same mechanism and adverse effects of leuprolide, our prototype GnRH agonist. Preparations, dosage, and administration are as follows:

• Triptorelin [Trelstar] is administered by IM injection. The recommended dosage is 3.75 mg once a month, 11.25 mg once every 3 months, or 22.5 mg once every 6 months.

• Goserelin [Zoladex] is formulated as pellets (3.6 mg and 10.8 mg) for subQ implantation in the upper abdominal wall. The 3.6-mg pellets are implanted every 4 weeks, and the 10.8-mg pellets are implanted every 12 weeks.

• Histrelin [Supprelin LA, Vantas] is formulated as a 50-mg pellet for subQ implantation in the inner aspect of the upper arm once every 12 months.

Gonadotropin-releasing hormone antagonists

Like the GnRH agonists, the GnRH antagonists suppress production of androgens by the testes. However, in contrast to the GnRH agonists, the GnRH antagonists do not produce an initial tumor flare. Currently, only one GnRH antagonist—degarelix—is available. An older drug—abarelix [Plenaxis]—has been withdrawn.

Degarelix

Degarelix [Firmagon], approved in 2009, is a synthetic decapeptide GnRH antagonist indicated for palliative therapy of advanced prostate cancer in men who are not candidates for a GnRH agonist, and who do not want surgical castration. Benefits derive from suppressing testosterone production by the testes. The underlying mechanism is blockade of GnRH receptors in the anterior pituitary, which decreases release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn deprives the testes of the stimulus they need for testosterone production. In clinical trials, patients received an initial 240-mg dose followed by monthly maintenance 80-mg doses. The result? Testosterone levels fell rapidly to those produced by castration, and then remained low for at least 12 months. Because degarelix works through direct blockade of GnRH receptors, the drug does not cause the initial surge in testosterone production seen with GnRH agonists, and hence there is no early tumor flare.

Degarelix is administered subQ, and absorption is slow. Plasma levels peak in 2 days. Elimination is primarily by peptide bond hydrolysis, a process that occurs in the liver but does not involve cytochrome P450 enzymes. The drug’s half-life is long: 53 days.

As with other drugs for ADT, major side effects are hot flushes, reduced libido, erectile dysfunction, gynecomastia, decreased muscle mass, and decreased bone mass with associated increased risk of fractures. In addition, degarelix often causes injection-site reactions (pain, erythema, swelling), weight gain, and elevation of liver transaminases. After a year of treatment, about 10% of patients develop antibodies against degarelix. However, the antibodies do not reduce the effectiveness of treatment. In contrast to abarelix (which has been withdrawn), degarelix does not cause severe, immediate-onset allergic reactions.

Degarelix is supplied as a powder (80 and 120 mg) to be reconstituted for subQ injection. The regimen consists of an initial 240-mg dose (two 120-mg injections), followed by monthly 80-mg injections for maintenance.

Androgen receptor blockers

Androgen receptor blockers, or simply antiandrogens, are indicated only for advanced androgen-sensitive prostate cancer—and only in combination with surgical castration or chemical castration using a GnRH agonist. Currently, three androgen receptor blockers are available: flutamide, bicalutamide, and nilutamide.

Flutamide

Flutamide, formerly available as Eulexin, is indicated for prostate cancer only. Benefits derive from blocking androgen receptors in tumor cells, thereby depriving them of needed androgenic support. In patients taking a GnRH agonist, flutamide can serve two purposes: (1) it can prevent tumor flare when GnRH therapy is started, and (2) it can block the effects of adrenal and prostatic androgens. As a rule, the combination of an androgen antagonist plus a GnRH agonist—so-called complete androgen blockade—is reserved for suppressing the initial flare and for suppressing the tumor after it has stopped responding to a GnRH agonist alone. The combination is not used continuously because it does not increase survival, but does increase toxicity.

Flutamide is administered orally and undergoes rapid and complete absorption. Most of each dose is converted to an active metabolite on the first pass through the liver. Parent drug and metabolites are excreted in the urine.

As with other drugs for ADT, prominent side effects are hot flushes, reduced libido, erectile dysfunction, gynecomastia, decreased muscle mass, and decreased bone mass with associated increased risk of fractures. Nausea, vomiting, and diarrhea are also common. Rarely, potentially fatal liver toxicity has occurred. To reduce the risk of serious harm, liver function should be assessed at baseline, monthly during the first 4 months of treatment, and periodically thereafter.

Flutamide may cause fetal harm, and hence is classified in FDA Pregnancy Risk Category D. Accordingly, the drug should not be used during pregnancy. Of course, since flutamide is approved only for prostate cancer, use during pregnancy should not happen anyway.

Flutamide is supplied in 125-mg capsules. The usual dosage is 250 mg three times a day.

Bicalutamide

Like flutamide, bicalutamide [Casodex] is an androgen receptor blocker used for advanced androgen-sensitive prostate cancer in men undergoing therapy with a GnRH agonist (eg, leuprolide). The rationale for the combination is explained in the discussion of flutamide. When bicalutamide is used alone, the most common side effects are breast pain (38%) and gynecomastia (39%). When the drug is combined with leuprolide, the most common side effect is hot flushes (49%). Like all other drugs used for ADT, bicalutamide can also cause reduced libido, erectile dysfunction, decreased muscle mass, and decreased bone mass with associated increased risk of fractures. Also, like flutamide, bicalutamide poses a small risk of liver injury, and hence liver function should be monitored. Bicalutamide poses a significant risk of fetal harm, and hence is classified in FDA Pregnancy Risk Category X. Bicalutamide is just as effective as flutamide, and dosing is more convenient (50 mg once a day vs. 250 mg 3 times a day). As a result, bicalutamide is preferred.

Nilutamide

Like flutamide and bicalutamide, nilutamide [Nilandron, Anandron] blocks receptors for androgens. The drug is approved for metastatic prostate cancer in men who have undergone surgical castration. Benefits derive from blocking the actions of adrenal androgens, which are not reduced by castration. In clinical trials, nilutamide reduced bone pain, prolonged progression-free survival, and increased median survival time. The recommended dosage is 300 mg once daily PO for 30 days followed by 150 mg once daily thereafter. Treatment should begin within 24 hours of castration.

Although nilutamide is structurally similar to flutamide, the drug is not as well tolerated. The most common adverse effects are hot flushes (67%), delayed adaptation to darkness (57%), nausea (24%), constipation (20%), insomnia (16%), and gynecomastia (11%). In addition, nilutamide can cause reduced libido, erectile dysfunction, decreased muscle mass, and decreased bone mass with associated increased risk of fractures. Other reactions occur less frequently, but are more dangerous. About 2% of patients experience dyspnea secondary to interstitial pneumonitis. If this develops, nilutamide should be withdrawn. About 1% of patients develop hepatitis. To ensure early diagnosis, liver function should be monitored.

Abiraterone, a cyp17 inhibitor

Actions and use.

Abiraterone [Zytiga], approved in 2011, is indicated for combined use with prednisone to treat metastatic castration-resistant prostate cancer in men previously treated with docetaxel. Benefits derive from inhibiting production of androgens by the adrenal gland and by the prostate cancer itself. (If castration has not been done, abiraterone can also inhibit androgen production by the testes.) In all cases, the underlying mechanism is inhibition of cytochrome P450 17 (CYP17), an enzyme needed by the adrenals, testes, and prostate tumors for androgen synthesis. When tested in men with metastatic castration-resistant prostate cancer, the combination of abiraterone plus prednisone increased overall survival by nearly 4 months, and progression-free survival by 2 months.

Adverse effects.

The most common adverse effects are hypokalemia (28.3%), edema (26.7%), joint swelling/discomfort (29.5%), muscle discomfort (26.2%), hot flushes (19%), diarrhea (17.6%), urinary tract infection (11.5%), cough (10.6%), and hypertension (8.5%). Like all other drugs for ADT, abiraterone can also decrease libido, muscle mass, and bone mass, and can cause erectile dysfunction and gynecomastia.

Inhibition of CYP17 in the adrenals can lead to overproduction of mineralocorticoids and underproduction of glucocorticoids. High levels of mineralocorticoids can cause retention of sodium and loss of potassium, leading to fluid retention, edema, hypertension, and hypokalemia. Low levels of glucocorticoids can increase the risk of death from traumatic events. Co-treatment with prednisone (a glucocorticoid) helps compensate for reduced production of glucocorticoids by the adrenals and, by suppressing release of adrenocorticotropic hormone from the pituitary, prednisone can reduce excessive production of mineralocorticoids.

Hepatotoxicity, manifesting as a marked elevation of liver transaminases—alanine aminotransferase (ALT) and aspartate aminotransferase (AST)—develops in about 30% of patients. To monitor liver status, ALT and AST should be measured at baseline, every 2 weeks for the first 3 months of treatment, and once a month thereafter. If these tests indicate significant liver injury, abiraterone should be discontinued or the dosage reduced.

Abiraterone can harm the developing fetus, and hence is classified in FDA Pregnancy Risk Category X. Accordingly, the drug should be avoided by women who are pregnant. Of course, since abiraterone is approved only for prostate cancer, use during pregnancy should not be an issue.

Drug interactions.

Abiraterone is a substrate for CYP3A4, and hence its levels can be raised by CYP3A4 inhibitors (eg, ketoconazole, clarithromycin, ritonavir), and lowered by CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin). Abiraterone inhibits hepatic CYP2D6, and hence can raise levels of CYP2D6 substrates (eg, dextromethorphan, thioridazine).

Preparations, dosage, and administration.

Abiraterone is supplied in 250-mg capsules, which should be swallowed with water on an empty stomach (1 hour before a meal or 2 hours after). Dosing should not be done with food, owing to greatly increased absorption, which could cause toxicity. The usual regimen is 1000 mg abiraterone once daily combined with 5 mg prednisone twice daily. Dosage of abiraterone should be reduced in patients with liver impairment.

Ketoconazole

Ketoconazole [Nizoral], used primarily for fungal infections (see Chapter 92), can be used off-label for prostate cancer. As with abiraterone, benefits derive from inhibiting testicular, adrenal, and prostatic production of androgens. Ketoconazole is employed as secondary therapy in men who have rising prostate-specific antigen levels despite treatment with a GnRH agonist plus an antiandrogen. Dosages are higher than those used for antifungal therapy (400 mg 3 times a day compared with 200 mg once a day), and hence side effects are common. Among these are nausea, vomiting, fatigue, skin changes, liver damage, and gynecomastia. Because high-dose ketoconazole can suppress adrenal production of glucocorticoids, the drug is usually combined with hydrocortisone (to avoid adrenal insufficiency).

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Tags: Pharmacology for Nursing Care

Jul 24, 2016 | Posted by admin in NURSING | Comments Off

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